Crystalline and amorphous solids of pantoprazole and processes for their preparation

Abstract

The present invention relates to a polymorphic form (Form I) of pantoprazole and a processes of making same. Form I has a PXRD pattern with characteristic peaks at 6.6, 13.2, 13.7, 15.7, 23.1, and 23.4±0.2 °2θ and a FTIR spectrum with characteristic bands at 1385, 1264, 1244, 1180, and 1027 at cm −1 . The process of making Form I includes crystallizing pantaoprazole or forming slurry from amorphous pantoprazole. The present invention also relates to another polymorphic form (Form II) of pantoprazole and a process of making the same. Form II has a PXRD pattern with characteristic peaks at 5.8, 7.5, 9.3, 15.0, 22.0, and 22.6±0.2 °2θ and a FTIR spectrum with characteristic bands at 3195, 1196, and 1584 at cm −1 . The process of making Form II includes forming a slurry from amorphous pantoprazole.

What is claimed is:  
     
         1 . Crystalline solid pantoprazole characterized by a powder X-ray diffraction pattern having peaks at 6.6, 13.2, 13.7, 15.7, 23.1, and 23.4±0.2 °2θ.  
     
     
         2 . The crystalline solid pantoprazole of  claim 1  further having peaks in the powder X-ray diffraction pattern at 20.1, 20.9, 25.9, 27.5, 29.1±0.2 °2θ.  
     
     
         3 . The crystalline solid pantoprazole of  claim 1  having a powder X-ray diffraction pattern substantially as depicted in FIG. 1.  
     
     
         4 . The crystalline solid pantoprazole of  claim 1  having an infrared spectrum with bands at 1385, 1264, 1244, 1180, and 1027 at cm −1 .  
     
     
         5 . The crystalline solid pantoprazole of  claim 4  having an infrared spectrum substantially as depicted in FIG. 2.  
     
     
         6 . A process for preparing the crystalline solid pantoprazole of  claim 1 , comprising 
 a) dissolving pantoprazole in a solvent;    b) precipitating crystals of the pantoprazole of  claim 1  from the solution; and    c) separating the crystals from the solvent.    
     
     
         7 . The process of  claim 6 , wherein the solvent is selected from the group consisting of ethanol, n-propanol, and acetone.  
     
     
         8 . The process of  claim 6 , wherein the solution is heated before precipitating the crystals.  
     
     
         9 . The process of  claim 8 , wherein the solution is then cooled to precipitate the crystals.  
     
     
         10 . A process for preparing the crystalline solid pantoprazole of  claim 1 , comprising 
 a) forming a slurry of amorphous pantoprazole in a diluent;    b) maintaining the slurry for a period of time sufficient to convert the amorphous pantoprazole to the pantoprazole of  claim 1;  and    c) separating the pantoprazole of  claim 1  from the diluent.    
     
     
         11 . The process of  claim 10 , wherein the slurry is maintained for at least twelve hours.  
     
     
         12 . The process of  claim 10 , wherein the diluent is selected from the group consisting of ethanol, acetone, n-propanol, ethyl acetate, tetrahydrofuran, sec-butanol, dimethylcarbonate, mixtures of methyl tert butyl ether and water, mixtures of dimethylcarbonate and water, mixtures of sec butanol and water, and mixtures of dichloromethane and water.  
     
     
         13 . Crystalline solid pantoprazole characterized by a powder X-ray diffraction pattern having peaks at 5.8, 7.5, 9.3. 15.0, 22.0, and 22.6±0.2 °2θ.  
     
     
         14 . The crystalline solid pantoprazole of  claim 13  further having peaks in the powder X-ray diffraction pattern at 17.3, 18.6, 19.4, 20.8, 24.0, 24.8, and 25.5±0.2 °2θ.  
     
     
         15 . The crystalline solid pantoprazole of  claim 13  having a powder X-ray diffraction pattern substantially as depicted in FIG. 3.  
     
     
         16 . The crystalline solid pantoprazole of  claim 13  having an infrared spectrum having bands at 3195, 1196, and 1584 at cm −1 .  
     
     
         17 . The crystalline solid pantoprazole of  claim 16  having an infrared spectrum substantially as depicted in FIG. 4.  
     
     
         18 . The crystalline solid pantoprazole of  claim 13  having a melting endotherm at about 143° C. to about 146° C.  
     
     
         19 . A process for preparing the crystalline solid pantoprazole of  claim 13 , comprising 
 a) forming a slurry of amorphous pantoprazole in a diluent;    b) maintaining the slurry for a period of time sufficient to convert the amorphous pantoprazole to the pantoprazole of  claim 13;  and    c) separating the pantoprazole of  claim 13  from the diluent.    
     
     
         20 . The process of  claim 19 , wherein the slurry is maintained for about twenty-four hours.  
     
     
         21 . The process of  claim 19 , wherein the solvent is selected from the group consisting of diethyl ether and tert-butyl methyl ether.  
     
     
         22 . A process for preparing a mixture of the crystalline solids pantoprazole of claims  1  and  13  comprising: 
 a) forming a slurry of amorphous pantoprazole in a diluent;  
 b) maintaining the slurry for a period of time sufficient to convert the amorphous pantoprazole to the pantoprazole of claims  1  and  13 ;  
 c) separating the pantoprazole of claims  1  and  13  from the diluent.  
 
     
     
         24 . The process of  claim 22 , wherein the slurry is maintained for at least about twenty-four hours.  
     
     
         25 . The process of  claim 22 , wherein the diluent is selected from the group consisting of mixtures of toluene and water, and methyl tert butyl ether.  
     
     
         26 . Amorphous pantoprazole.  
     
     
         27 . A process for preparing the amorphous pantoprazole of  claim 26 , comprising 
 a) partitioning pantoprazole between the organic and aqueous phases of a biphasic mixture of a water-immiscible organic liquid and water;    b) adding acid to the mixture;    c) separating the organic phase and the water; and    d) recovering amorphous pantoprazole from the organic phase.    
     
     
         28 . The process of  claim 27 , wherein pantoprazole is partitioned by adding pantoprazole sodium to the mixture.  
     
     
         29 . The process of  claim 27 , wherein the amorphous pantoprazole is recovered by evaporating the organic liquid.  
     
     
         30 . The process of  claim 27 , wherein the organic liquid is dichloromethane.  
     
     
         31 . The process of  claim 27 , wherein the acid is acetic acid.  
     
     
         32 . A process for preparing a salt of pantoprazole comprising converting the pantoprazole of any of claims  1 ,  13 , and  26  to a salt of pantoprazole.  
     
     
         33 . A salt of pantoprazole prepared by the process of  claim 32 .  
     
     
         34 . The process of  claim 32 , wherein the salt is pantoprazole sodium.  
     
     
         35 . Pantoprazole sodium prepared by the process of  claim 34 .  
     
     
         36 . A process for preparing a salt of pantoprazole comprising: 
 a) stirring pantoprazole of any of claims  1 ,  13 , and  26  with ethyl acetate and aqueous sodium hydroxide; and    b) isolating pantoprazole sodium.    
     
     
         37 . Pantoprazole sodium prepared by the process of  claim 36 .  
     
     
         38 . The product of  claim 37 , wherein the pantoprazole sodium is sesquihydrate.  
     
     
         39 . The process of  claim 36 , wherein the pantoprazole is the pantoprazole of  claim 1 .  
     
     
         40 . The process of  claim 36 , wherein the mixture is stirred overnight at room temperature.  
     
     
         41 . A pharmaceutical composition comprising the pantoprazole of any of claims  1 ,  13 , and  26  and a pharmaceutical excipient.  
     
     
         42 . The pharmaceutical composition of  claim 41  that is a solid.  
     
     
         43 . The pharmaceutical composition of  claim 42  that is a tablet.  
     
     
         44 . The pharmaceutical composition of  claim 41  that is a liquid.  
     
     
         45 . A method of inhibiting gastric acid secretion in the stomach of a patient comprising administering to the patient the pantoprazole of any of claims  1 ,  13 , and  26 .  
     
     
         46 . A pharmaceutical composition comprising the pantoprazole of any of claims  33 ,  37  and  38  and a pharmaceutical excipient.  
     
     
         47 . The pharmaceutical composition of  claim 46  that is a solid.  
     
     
         48 . The pharmaceutical composition of  claim 47  that is a tablet.  
     
     
         49 . The pharmaceutical composition of  claim 46  that is a liquid.  
     
     
         50 . A method of inhibiting gastric acid secretion in the stomach of a patient comprising administering to the patient the pantoprazole of any of claims  33 ,  37 , and  38 .